tbuckley/cabot-search huggingface dataset:
Abstract 5114: Development of personalized RNA-based immunotherapeutics for glioblastom
Authors: Vrunda Trivedi, Changlin Yang, Oleg Yegorov, Kelena Klippel, Graeme Fenton, Christina von Roemeling, Lan Hoang-Minh, Elizabeth Ogando-Rivas, Paul Castillo, Kyle Dyson, Ginger Moore, Duane Mitchell
Journal: Cancer Research (2023)

Abstract Background: The development of successful immunotherapy targeting antigens in glioblastoma multiforme (GBM) remains a challenge owing to antigen heterogeneity and the low mutation burden in GBM. Cancer immunogenomics represents a complementary approach to the application of genomics in developing novel immunotherapies for GBM. Our goal is to develop a personalized RNA-based therapeutic vaccine that simultaneously targets a selected pool of tumor rejection antigens including all neoantigens and tumor-associated antigens (TAAs) as identified using cancer immunogenomics. We evaluated the treatment efficacy of these RNA therapeutics in combination with adoptive cellular therapy and checkpoint inhibitors. Methods: We identified immunogenic neoantigens and TAAs that are aberrantly overexpressed in KR158-luc and GL261 murine GBM tumors using our cancer immunogenomics pipeline called the Open Reading Frame Antigen Network (O.R.A.N.). A tumor antigen-specific RNA library was created for each tumor using a novel gene enrichment strategy and validated by RNAseq. Tumor-bearing animals were treated with adoptively transferred ex vivo expanded lymphocytes and dendritic cells loaded with the tumor antigen-specific RNA as vaccines. Additionally, we treated animals with the tumor antigen-specific RNA vaccines in combination with anti-PD-1 checkpoint-blockade therapy. Tumor progression and survival outcomes were analyzed to evaluate the treatment efficacies. We determined the peripheral and tumor-infiltrating lymphocyte responses using flow cytometry, TCR sequencing, and single cell RNAseq. Results: The tumor antigen-specific RNA vaccines were significantly effective in slowing the progression of murine GBM tumors in combination with both the adoptive cellular therapy and the checkpoint blockade therapy and improved the outcome of these therapies as compared to monotherapy alone. Additionally, we identified antigen-specific T cells targeting several of our predicted antigens and an increase in tumor-infiltrating lymphocytes and memory T cells in the treated animals. Conclusion: Here, we developed an RNA-based immunotherapy that simultaneously targets numerous tumor-specific antigens and demonstrated its therapeutic efficacy in preclinical models of GBM. Citation Format: Vrunda Trivedi, Changlin Yang, Oleg Yegorov, Kelena Klippel, Graeme Fenton, Christina von Roemeling, Lan Hoang-Minh, Elizabeth Ogando-Rivas, Paul Castillo, Kyle Dyson, Ginger Moore, Duane Mitchell. Development of personalized RNA-based immunotherapeutics for glioblastom. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5114.
Abstract 3495: A kinome-wide CRISPR screen identifies CK1α as a novel target to overcome enzalutamide resistance of prostate cancer
Authors: Jinghui Liu, Yue Zhao, Derek Allison, Daheng He, Lang Li, Xiaoqi Liu
Journal: Cancer Research (2023)

Abstract Background: Androgen deprivation therapy is the first line of therapy for localized prostate cancer (PCa), but most patients will eventually develop castration-resistant PCa (CRPC). Enzalutamide (ENZA), a second-generation androgen receptor (AR) antagonist, has significantly increased CRPC patient survival. However, resistance remains a prominent obstacle in treatment, illustrating the urgent need to develop new approaches to increase ENZA efficacy. Methods: A Kinome-wide CRISPR-Cas9 screen was used to identify the targets related to ENZA response. In vitro cell viability and in vivo cell line or patient-derived xenografts were used to verify inhibiting CK1α overcoming ENZA resistance. RNA sequencing was used to address the functions of CK1α in ENZA resistance. In vitro kinase assay was used to study ATM phosphorylation by CK1α. Immunohistochemistry, immunofluorescence, immunoblot and immunoprecipitation assays were used to study the functions of CK1α in regulation of ATM and DNA damage response signaling. Bioinformatics analysis was used to confirm these findings with clinical patients’ database. Results: Utilizing a kinome-wide CRISPR-Cas9 knockout screen, we identified casein kinase 1 alpha (CK1α) as a novel therapeutic target to overcome ENZA resistance. Depletion or pharmacologic inhibition of CK1α with a novel compound in clinical trial significantly enhanced EZNA efficacy in ENZA resistant cell lines and patient-derived xenografts. Mechanistically, CK1α phosphorylates the serine residue S1270 and modulates the protein abundance of ataxia-telangiectasia mutated (ATM), which is a primary initiator of DNA double-strand break (DSB)-response signaling, and is compromised in ENZA-resistant cells and patients. Inhibition of CK1α stabilizes ATM, resulting in the restoration of DSB-response signaling, and thus increases ENZA-induced cell death and growth arrest in an ATM-dependent manner. Conclusions: Our study details an innovative therapeutic approach for ENZA-resistant PCa and characterizes a novel perspective for the function of CK1α in the regulation of DNA damage response signaling through phosphorylation of ATM S1270. Citation Format: Jinghui Liu, Yue Zhao, Derek Allison, Daheng He, Lang Li, Xiaoqi Liu. A kinome-wide CRISPR screen identifies CK1α as a novel target to overcome enzalutamide resistance of prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3495.
Abstract 5954: Germline epitopes modulate immune surveillance informing breast cancer subtypes
Authors: Kathleen Houlahan, Aziz Khan, Christina Curtis
Journal: Cancer Research (2023)

Abstract Cancer represents a wide spectrum of molecularly and morphologically diverse diseases. Individuals with the same histopathological classification can have tumors with drastically different molecular profiles and clinical responses to treatment. It remains unclear as to when during the disease course these differences arise and why some tumors are addicted to one oncogenic pathway over another. Somatic genomic aberrations occur within the context of an individual’s germline genome, which can vary across millions of germline polymorphisms. It is unknown the extent to which germline differences influence the somatic evolution of a tumor. Interrogating 4,912 breast cancer lesions, spanning pre-invasive to metastatic disease, we demonstrate that germline variants in highly expressed and amplified genes influence somatic evolution by modulating immunoediting at early stages of tumor development. Specifically, we show that the burden of germline-derived epitopes in recurrently amplified genes selects against somatic gene amplification in pre-invasive and invasive breast cancer. As a representative example, individuals with high burden of germline-derived epitopes in ERBB2 are significantly less likely to develop HER2+ breast cancer than ER+ or triple negative breast cancer. The same negative association between epitope burden and somatic amplification is observed for four recurrent amplicons observed in high risk ER+ breast tumors. No association was observed between somatic amplifications and epitope burden in metastatic breast cancer suggesting a subset of tumors are able to overcome immune-mediated negative selection. Tumors that do are more aggressive and demonstrate an “immune cold” phenotype. Taken together, these data show the germline genome plays a pivotal role in dictating somatic evolution in breast cancer. Exploiting germline-mediated immunoediting may facilitate the development of blood-based biomarkers that refine risk stratification within breast cancer subtypes. Citation Format: Kathleen Houlahan, Aziz Khan, Christina Curtis. Germline epitopes modulate immune surveillance informing breast cancer subtypes. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5954.
Abstract 2414: Early biological impacts of radiotherapy-activated NBTXR3 nanoparticles
Authors: Jordan Da Silva, Célia Bienassis, Sebastien Paris
Journal: Cancer Research (2023)

Abstract Since many decades, radiotherapy (RT) is worldwide used and crucial therapeutic approach for the treatment of cancers. Nowadays, about 50% of cancer patients will receive radiotherapy during their treatment. Nevertheless, the use of RT is limited by the damage induced by ionizing radiation on healthy tissues. To overcome this constraint, we have developed high electron density of functionalized hafnium oxide nanoparticles (NBTXR3), allowing a high probability of interaction with incoming ionizing radiation, increasing energy dose deposit within cells. Many preclinical data have shown that RT-activated NBTXR3 (NBTXR3+RT) increase cancer cell destruction as well as better control treated tumor growth, compared to RT alone. In clinic, the benefit of NBTXR3+RT compared to RT alone has been demonstrated for patients with locally advanced Soft Tissue Sarcoma, in the randomized controlled phase II/III Act.in.Sarc study (NCT02379845). We also demonstrated in preclinical settings that, beyond the destruction of tumor cells, NBTXR3+RT was also able to induce an antitumor immune response capable to produce a significant abscopal effect, linked to the increase of CD8 infiltrates in tumors. It has been recently reported that NBTXR3+RT can also restore anti-PD1 efficacy in an anti-PD1 resistant mouse model. At the cancer cell level, we reported that NBTXR3+RT could modulate the immunopeptidome of cancer cells, induce the activation of the cGAS-STING pathway and increase the expression of ICD biomarkers. All these data indicate that NBTXR3+RT has the ability to transform the tumor into an in situ vaccine more efficiently than RT alone and could have important implications for the use of NBTXR3+RT in combination with immunotherapy. Nevertheless, we currently have relatively few elements on the early cellular events that could trigger or explain the above reported performances of NBTXR3+RT, compared to RT alone. To address this question, we have carried out a series of in vitro studies (cytometry, microscopy) on different cancer models (human and murine). We have thus identified that the vast majority of NBTXR3 nanoparticles are located in lysosomes after endocytosis by tumor cells. Once activated by RT, we detected lysosomal membrane permeabilization (LMP) only in cells treated with NBTXR3+RT, but not in cells only treated by RT. Following LMP, we measured a significant increase of in lipid peroxidation. These first elements allow a better understanding of the early biological consequences induced by NBTXR3+RT, compared to RT alone. Citation Format: Jordan Da Silva, Célia Bienassis, Sebastien Paris. Early biological impacts of radiotherapy-activated NBTXR3 nanoparticles [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2414.
Abstract 4480: Treatment of PTEN/PI3K co-mutated endometrial adenocarcinoma with multitarget small molecule inhibitors
Authors: Ritchie Delara, Cody McHale, Dhananjaya Pal, Krishnaiah Maddeboina, R. Wendel Naumann, Erin Crane, Jubilee Brown, Donald Durden
Journal: Cancer Research (2023)

Abstract Introduction: The objective of this study is to assess the feasibility and safety of treating endometrial adenocarcinoma (EC) with multitarget inhibitors which orthogonally target known oncogenic kinases and epigenetic regulators. The Molecular Targeted Therapeutics Laboratory has developed nanomolar potent multitarget small molecule chemotypes that inhibit the PI3K/Akt/mTOR pathway, cancer-associated kinases, and epigenetic regulatory proteins such as BRD4 in vitro and in vivo. Methods: Two EC cell lines (AN3-CA, RL95-2) were treated with varying concentrations of triple PI3K/BRD4/CDK4/6/9 inhibitor LCI132 and dual PI3K/CDK4/6/9 inhibitors LCI133 and LCI136 for 48 hours; and cell viability assays were performed with IC50 determination. EC cells were treated with multitarget inhibitors and other indicated inhibitors of PI3K, BET, CDK4/6, and CDK9 for 24 hours; and lysates were prepared accordingly for Western blot (WB) and qRT-PCR analyses. Flow cytometry was conducted for cell cycle and apoptosis assays. Results: In cell-free assays, LCI132 is a nanomolar inhibitor of PI3K/BRD4/CDK4/6/9, LCI133 is a picomolar inhibitor of CDK9, and LCI136 is a nanomolar inhibitor of PI3K and CDK9. LCI133 demonstrated nanomolar potency towards AN3-CA (IC50 248 nM) and RL95-2 (IC50 105 nM). LCI136 demonstrated nanomolar potency towards AN3-CA (IC50 631 nM) and RL95-2 (IC50 728 nM). WB demonstrated 24-hour treatment of FBXW7mut AN3-CA with LCI132 inhibited AKT phosphorylation but an increase in c-MYC protein expression. A corresponding increase in c-Myc gene expression at 24 hours was confirmed on qRT-PCR. In FBXW7wt RL95-2, LCI132 decreased c-Myc protein expression. LCI132 demonstrated dose-dependent G1 arrest, and dose-dependent pre-apoptotic and apoptotic activity. Conclusions: Dual-target inhibitors LCI133 and LCI136 are nanomolar potent in AN3-CA and RL95-2 EC cell lines, suggesting a role of CDK9 inhibition of PTEN/PI3K co-mutated EC. Preliminary studies demonstrate an upregulation of MYC gene and protein expression in FBXW7mut EC but not FBXW7wt, and the role of FBXW7 as a predictive biomarker in treatment of PTEN/PIK3R1 co-mutated EC warrants further investigation. Citation Format: Ritchie Delara, Cody McHale, Dhananjaya Pal, Krishnaiah Maddeboina, R. Wendel Naumann, Erin Crane, Jubilee Brown, Donald Durden. Treatment of PTEN/PI3K co-mutated endometrial adenocarcinoma with multitarget small molecule inhibitors. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4480.
Abstract PL03-02: When to intervene along the breast cancer continuum?
Authors: E. Shelley Hwang
Journal: Cancer Research (2023)

Abstract Advances in epidemiology and cancer biology have clearly established that the group of diseases currently deemed “cancers” in fact encompasses many conditions with enormous variation in biologic behavior. Decades of cancer screening have preferentially diagnosed early, asymptomatic, indolent lesions. This trend will only increase as screening technologies become ever more sensitive, leading to an epidemic of overtreatment in completely asymptomatic individuals. The treatment of many of these conditions often has uncertain benefit on cancer mortality, while coming at the clear cost of treatment-related morbidity. Multi-omic testing plays a role in refining treatment recommendations based upon risk of progression. Genomic profiling of accurately annotated longitudinal case control datasets have provided insights into breast lesions termed “ductal carcinoma in situ” (DCIS), which are thought to be precursors to invasion and metastases. Both transcriptomics as well spatially resolved proteomic characterization of DCIS have uncovered novel biology of the epithelial cells that make up DCIS, as well as the heterogeneous precancer ecosystems which can be either permissive or inhibitory for invasion. Recent work has uncovered a clonal evolution pathway characterized by multiclonal invasion, and has helped to build risk stratification tools to refine treatment recommendations. In addition to molecular characterization, risk modeling may yield insights about which patients derive greatest benefit from intervention. For asymptomatic tumors at low risk of cancer progression, there may be little to no benefit to treatment, whereas for more high-risk lesions, progression to invasion and metastasis may be rapid and deadly. Given the lead-time between the development of precancer and progression to invasive disease, there may also be a case for tailoring intervention of screen detected cancer by age and the presence of competing comorbidities. The decision of whether and when to intervene for screen-detected cancers will require a multidisciplinary effort including expertise in cancer biology, mathematical modeling, psychology, health policy, decision science and communication, as well as thoughtful engagement from patients and health care providers to identify the optimal time to intervene along the cancer progression continuum. Citation Format: E. Shelley Hwang. When to intervene along the breast cancer continuum?. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr PL03-02.
Abstract 415: Metabolic reprogramming driven by IGF2BP3-COX6B2 axis promotes acquired resistance to EGFR-TKIs in non-small lung cancer
Authors: Ziyou Lin, Jingwei Li, Jian Zhang, Weineng Feng, Jiaye Lu, Xiaofan Ma, Wen Ding, Shumin Ouyang, Jinjian Lu, Peibin Yue, Guohui Wan, Peiqing Liu, Xiaolei Zhang
Journal: Cancer Research (2023)

Abstract Acquired resistance represents a bottleneck to molecular targeted therapy in lung cancer. Metabolic adaptation is a distinct hallmark of human lung cancer, but its role in acquired resistance has not been fully understood. In this study, we discovered a novel mechanism of TKI resistance involved in IGF2BP3-dependent crosstalk between the epigenetic modifications and metabolic reprogramming through the IGF2BP3-COX6B2 axis. We demonstrated the upregulated expression of RNA binding protein IGF2BP3 reduced the sensitivity of TKI treatment and exacerbated the development of drug resistance via promoting oxidative phosphorylation (OXPHOS). Analysis of patient samples revealed a positive correlation between IGF2BP3 and COX6B2 and poor prognosis in lung cancer patients. We further confirmed that COX6B2 is a key downstream target in IGF2BP3-mediated acquired TKI-resistance. Mechanistically, IGF2BP3 bound to the 3’-untranslated region of COX6B2 in an m6A-dependent manner to increase COX6B2 mRNA stability. Moreover, IGF2BP3 significantly enhanced OXPHOS capacity in lung cancer through the IGF2BP3-COX6B2 axis by regulating nicotinamide metabolism, thus resulting in TKI resistance in lung cancer. Inhibition of OXPHOS with IACS-010759, a small-molecule inhibitor, resulted in remarkable growth inhibition in vitro and in vivo in a gefitinib-resistant patient-derived xenograft model. Collectively, our findings suggest that metabolic reprogramming directed by the IGF2BP3-COX6B2 axis plays a critical role in TKI resistance, and targeting the metabolic pathway provides a new therapeutic strategy to overcome EGFR-TKI resistance in lung cancer. Citation Format: Ziyou Lin, Jingwei Li, Jian Zhang, Weineng Feng, Jiaye Lu, Xiaofan Ma, Wen Ding, Shumin Ouyang, Jinjian Lu, Peibin Yue, Guohui Wan, Peiqing Liu, Xiaolei Zhang. Metabolic reprogramming driven by IGF2BP3-COX6B2 axis promotes acquired resistance to EGFR-TKIs in non-small lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 415.
Abstract 4242: High sugar food consumption and breast cancer risk in a prospective cohort study
Authors: Woo-Kyoung Shin, Dan Huang, Katherine De la Torre, Sukhong Min, Aesun Shin, Jong-koo Lee, Wonshik Han, Jung Eun Lee, Daehee Kang
Journal: Cancer Research (2023)

Abstract Background: The association between excessive sugar intake and the risk of breast cancer has been considered in epidemiologic studied, however, the results are unclear. This study examined to evaluated between high-sugar food intake and breast cancer in a prospective cohort study. Methods: This prospective cohort study included a total of 71,266 women aged 40-69 years from the Health Examinees-Gem (HEXA-G) study between 2004 and 2013. Information on cancer diagnosis was retrieved from the Korea Central Cancer Registry until 31 December 2018. Multivariate hazard ratios (HRs) and 95% of confidence intervals (CIs) for the risk of gastric cancer according to the consumption of high-sugar food were estimated using Cox proportional hazards models with age as the time scale. Results: A total of 713 incident cases of breast cancer occurred over an average follow-up period of 9.20 years. The top food contributing to total sugar intake was fruit (42.89%). We found that increased consumption of sugary cereal was associated with increased risk of breast cancer; HR for sugary cereal consumption of more than one servings/two months vs. almost never consumed was 1.34 (95% CI: 1.08, 1.65; p for trend = 0.01). Also, consumption of loaf bread (p for trend = 0.03), ice cream (HR for ice cream consumption of more than one servings/week vs. almost never consumed = 1.26; 95% CI: 1.00, 1.58; p for trend = 0.03), and added sugar food (HR for all sugary food groups consumption of more than two servings/week vs. less than one serving/month consumed =1.28; 95% CI: 1.02, 1.61; p for trend = 0.05) was associated with increased risk of breast cancer. Conclusion: Our results suggest that a high-sugar food consumption was associated with an increased risk of breast cancer among Korean women. Key words: Sugar, High-sugar foods, Breast cancer, the Health Examinees (HEXA) study, prospective cohort study. Citation Format: Woo-Kyoung Shin, Dan Huang, Katherine De la Torre, Sukhong Min, Aesun Shin, Jong-koo Lee, Wonshik Han, Jung Eun Lee, Daehee Kang. High sugar food consumption and breast cancer risk in a prospective cohort study. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4242.